Risks of Topical Tretinoin Use During Pregnancy and Breastfeeding

Introduction

Tretinoin (all-trans retinoic acid) is a topical retinoid widely used for acne and skin aging. Because of its similarity to oral retinoids like isotretinoin (referred from here on out as ISO-tretinoin for emphatic distinction), the safety of topical tretinoin during pregnancy has been a concern.  

ISO-tretinoin (13-cis retionic acid) is a similar but distinctly different medication than tretinoin. (Tretinoin: What Is It?) ISO-tretinoin is a well-documented human teratogen associated with a distinct pattern of congenital malformations. These include:

• Craniofacial structural defects, such as micrognathia, cleft palate, and anotia/microtia (Choi et al., 2021; Alay et al., 2023).

• Cardiovascular system defects, including conotruncal heart defects, ventricular septal defects (VSD), atrial septal defects (ASD), and transposition of the great arteries (Alay et al., 2023).

• Central nervous system defects, notably neural tube defects, corpus callosum dysgenesis, hydrocephalus, and facial paralysis (Alay et al., 2023).

• Defects of the thymus, leading to immunological and developmental impairments (Choi et al., 2021).

• Genitourinary abnormalities, such as hypospadias and undescended testes (Alay et al., 2023).

  
  

Approximately 15–28.6% of live-born babies exposed to ISO-tretinoin during pregnancy were found to have major congenital malformation (Choi et al., 2021; Alay et al., 2023). However, it is important to note that this number does not include pregnancies that were electively terminated due to concerns about birth defects, meaning the true risk could be higher. Earlier studies, before strict pregnancy prevention programs were in place, reported major malformation rates as high as 30% (Choi et al., 2021).

Furthermore, even in cases where a baby is born without major visible birth defects, studies suggest that neurodevelopmental issues, such as learning disabilities and behavioral problems, may still occur in up to 30% of exposed fetuses (Alay et al., 2023). This means that even if the baby appears physically healthy, there could still be risks to brain development that might not be immediately obvious at birth.

Although studies suggest that the risk of birth defects may be lower with shorter exposure durations and lower doses (Choi et al., 2021), other data refute this claim. (Alay et al., 2023)  Perhaps most importantly, no level of ISO-tretinoin is considered safe during pregnancy.

Topical Tretinoin Use in Pregnancy: Initial Concerns and Case Reports

Early case reports raised alarms by describing infants with malformations born to mothers who had used topical tretinoin during the first trimester which resembled those with retinoic acid embryopathy seen with systemic ISO-tretinoin exposure. (Camera and Pregliasco, 1992; Selcen et al, 2000). In an appropriate abundance of caution, this prompted clinicians to generally advise against topical tretinoin in pregnancy.

Evidence from Clinical Studies (Pregnancy Outcomes)

Subsequent larger studies have provided more data on pregnancy outcomes after topical tretinoin exposure. Across five studies analyzing over 1,200 exposed pregnancies compared to more than 2,500 unexposed controls, major congenital malformations occurred in 1.9%–3.5% of exposed pregnancies, closely matching the control rates (1.2%–3.3%). Spontaneous abortion rates ranged from 6.4% to 8.1% in exposed groups, similar to control rates (5.9%–9.0%), while stillbirths were extremely rare in both groups (0%–2.1%). The elective termination rate was higher in some exposed groups (up to 6.4% vs. 1.6% in controls), likely due to maternal concerns rather than confirmed fetal abnormalities.

Study (Exposure)	Sample Size (Cases/Controls)	Major Malformations (Cases vs. Controls, %)	Spontaneous Abortion (Cases vs. Controls, %)	Stillbirth (Cases vs. Controls, %)	Elective Termination (Cases vs. Controls, %)
Jick et al., 1993 (topical tretinoin)	215 / 430	1.9% (4/212) vs. 2.6% (11/427)	Not reported	1.4% (3/218) vs. 0.5% (2/430)	Not reported
Shapiro et al., 1997 (topical tretinoin)	94 / 133	2.3% (2/86) vs. 3.3% (4/119)	6.4% (6/94) vs. 9.0% (12/133)	0% vs. 0%	3.2% (3/94) vs. 1.5% (2/133)
Loureiro et al., 2005 (topical tretinoin)	106 / 389	2.2% (2/91) vs. 1.2% (4/322)	6.6% (7/100) vs. 8.5% (33/368)	0% vs. 0%	2.0% (2/100) vs. 3.5% (13/368)
Panchaud et al., 2012 (various topical retinoids)	235 / 444	3.5% (8/201) vs. 2.2% (9/410)	8.1% (19/235) vs. 5.9% (26/444)	0% vs. 0.2% (1/444)	6.4% (15/235) vs. 1.6% (7/444)
Kaplan et al., 2015 (various topical retinoids)	590 / 1375	1.22% (cases) vs. ~1.0% (controls) (OR: 1.22, CI: 0.65–2.29)	1.02% (cases) vs. ~1.0% (controls) (OR: 1.02, CI: 0.64–1.63)	2.06% (cases) vs. ~1.0% (controls) (OR: 2.06, CI: 0.43–9.86)	1.89% (cases) vs. ~1.0% (controls) (OR: 1.89, CI: 0.52–6.80)

Overall, these human studies consistently indicate no observable teratogenic effect from topical tretinoin when used in early pregnancy. Crucially, none of the larger trials found any pattern of birth defects resembling retinoic acid syndrome in exposed infants. Rates of major malformations in exposed pregnancies were roughly in line with the baseline ~3% risk present in the general population. Likewise, measures of fetal growth (birth weight, head circumference) and timing of delivery did not differ between exposed and unexposed groups. These data suggest that any systemic absorption from topical tretinoin is too low to cause the profound embryonic damage seen with systemic retinoids.

Safety Concerns and Clinical Recommendations in Pregnancy

Despite the generally reassuring evidence, professional recommendations remain cautious. (ACOG; McMullan et al, 2024) The theoretical risk of even low-level retinoid exposure has led to a “better safe than sorry” approach. Tretinoin is traditionally classified as FDA Pregnancy Category C (risk cannot be ruled out), reflecting that animal studies at high doses showed teratogenic effects. (FDA, Retin-A)   Given these concerns, most dermatologists advise avoiding topical tretinoin during pregnancy, especially when used for purely cosmetic purposes like reduction of photoaging. However, the lack of evidence supporting harm in the event of inadvertent exposure is important in providing reassuring counseling during such a scenario. 

Pharmacokinetics and Fetal Exposure

Understanding tretinoin’s pharmacokinetics helps explain why topical use has little apparent fetal impact. Tretinoin applied to the skin results in minimal systemic absorption. In pharmacokinetic studies, only about 2% of a topically applied dose was absorbed into circulation, even after 28 days of daily use. With long-term use (over 1 year), absorption averaged just ~1.1% of the dose. Importantly, mean plasma concentrations of tretinoin in subjects after topical treatment were no different from normal endogenous retinoic acid levels prior to treatment. In other words, standard topical application did not appreciably raise the level of retinoids in the blood above what is naturally present. (Latriano et al, 1997)

Tretinoin also has a short half-life and does not accumulate significantly in the body. In healthy adults, most of a given dose is eliminated within about one day. (FDA, Vesanoid) This rapid clearance further limits fetal exposure. By contrast, oral ISO-tretinoin produces much higher systemic levels that persist longer, hence its well-known teratogenicity. Topical tretinoin’s low percutaneous absorption and swift metabolism mean that the placenta is exposed to only trace amounts of the drug. The lack of any retinoid embryopathy cases among hundreds of exposed pregnancies supports the conclusion that fetal exposure levels remain below the threshold for teratogenic effects. That said, pharmacokinetic absorption can increase in certain scenarios. It is generally accepted that application to skin with compromised barrier, to large surface areas, or use of occlusive dressings over top the applied surface can enhance percutaneous drug uptake.

Breastfeeding and Lactation Considerations

There is very limited direct research on topical tretinoin use during breastfeeding, but the pharmacokinetic data suggest that only minimal drug would transfer into breast milk. In a review of the safety of dermatologic medications in pregnancy and lactation, the authors state that topical tretinoin is considered likely safe for use during breastfeeding due to its negligible systemic absorption, which makes it unlikely to be excreted into breast milk in significant amounts. While vitamin A is excreted in breast milk, because of the low systemic absorption any tretinoin that does transfer is expected to be in trace amounts, posing minimal risk to the nursing infant. As a precaution, the paper recommends avoiding application to the nipple area to prevent direct infant exposure. Overall, the evidence suggests that topical tretinoin is likely safe during lactation when applied appropriately. (Yaghi et al, 2024)

Conclusion

The collective evidence from human studies strongly suggests that topical tretinoin does not pose a significant teratogenic risk during pregnancy. Unlike oral ISO-tretinoin, which is a well-documented teratogen, topical tretinoin exhibits minimal systemic absorption, and clinical research has not identified an increased risk of major birth defects, spontaneous abortion, or stillbirth in exposed pregnancies compared to unexposed controls. Rates of congenital malformations (1.9%–3.5%) in tretinoin-exposed pregnancies closely align with baseline rates observed in the general population (~3%), reinforcing the conclusion that fetal exposure from topical use is insufficient to cause the severe embryopathy associated with systemic retinoids.

However, the key safety message is that the absence of evidence of harm is not absolute proof of safety, so prudence dictates avoiding tretinoin in pregnant patients – even though the actual risk, if any, appears to be extremely low. Current professional recommendations (ACOG; McMullan et al, 2024) advise avoiding tretinoin during pregnancy, especially for elective cosmetic use, following the principle of "better safe than sorry." However, in cases of inadvertent exposure, the available evidence provides strong reassurance that the likelihood of harm is extremely low. Similarly, in breastfeeding mothers, the negligible systemic absorption suggests minimal risk to the infant.

In summary, topical tretinoin is not contraindicated due to direct evidence of harm, but due to a lack of absolute safety data, avoidance during pregnancy remains the conservative recommendation.

Dr. Ryan M. Trowbridge, MD, MS, MA

Harvard-Trained, Board-Certified Dermatologist and DermMythBuster

P.S. Have you come across any new or conflicting research on this topic? Please share—I’d love to explore it further with you!

Have skin concern? You can obtain an online consultation from Dr. Trowbridge at Bridge Dermatology if you currently reside in California, Connecticut, Illinois, or Nebraska.

Citations

1. Alay MT, Kalayci A, Seven M. A new perspective on isotretinoin in pregnancy: Pregnancy outcomes, evaluation of complex phenotypes, and importance of teratological counselling. Eur J Obstet Gynecol Reprod Biol. 2023;291:148-155.

2. American College of Obstetricians and Gynecologists. Skin Conditions During Pregnancy. ACOG. Accessed March 6, 2025. https://www.acog.org/womens-health/faqs/skin-conditions-during-pregnancy.

3. Camera G, Pregliasco P. Ear malformation in baby born to mother using tretinoin cream. Lancet. 1992;339(8794):687. doi:10.1016/0140-6736(92)90854-v

4. Choi EJ, Kim NR, Kwak HS, et al. The rates of major malformations after gestational exposure to isotretinoin: a systematic review and meta-analysis. Obstet Gynecol Sci. 2021;64(4):364-373. doi:10.5468/ogs.20373

5. Kaplan YC, Ozsarfati J, Etwel F, Nickel C, Nulman I, Koren G. Pregnancy outcomes following first-trimester exposure to topical retinoids: a systematic review and meta-analysis. Br J Dermatol. 2015;173(5):1132-1141. doi:10.1111/bjd.14053

6. Latriano L, Tzimas G, Wong F, Wills RJ. The percutaneous absorption of topically applied tretinoin and its effect on endogenous concentrations of tretinoin and its metabolites after single doses or long-term use. J Am Acad Dermatol. 1997;36(3 Pt 2):S37-S46. doi:10.1016/s0190-9622(97)70059-8

7. Loureiro KD, Kao KK, Jones KL, et al. Minor malformations characteristic of the retinoic acid embryopathy and other birth outcomes in children of women exposed to topical tretinoin during early pregnancy. Am J Med Genet A. 2005;136(2):117-121. doi:10.1002/ajmg.a.30744

8. McMullan P, Yaghi M, Truong TM, Rothe M, Murase J, Grant-Kels JM. Safety of dermatologic medications in pregnancy and lactation: An update - Part I: Pregnancy. J Am Acad Dermatol. 2024;91(4):619-648. doi:10.1016/j.jaad.2023.10.072

9. Panchaud A, Csajka C, Merlob P, et al. Pregnancy outcome following exposure to topical retinoids: a multicenter prospective study. J Clin Pharmacol. 2012;52(12):1844-1851. doi:10.1177/0091270011429566

10. Patel V, et al. Safety of topical dermatologic medications in pregnancy. J Drugs Dermatol. 2016;15(7):830-836.

11. Selcen D, Seidman S, Nigro MA. Otocerebral anomalies associated with topical tretinoin use. Brain Dev. 2000;22(4):218-220. doi:10.1016/s0387-7604(00)00104-2

12. Shapiro L, Pastuszak A, Curto G, Koren G. Safety of first-trimester exposure to topical tretinoin: prospective cohort study. Lancet. 1997;350(9085):1143-1144. doi:10.1016/S0140-6736(05)63790-7

13. U.S. Food and Drug Administration. Tretinoin (Retin-A) drug label. Updated 2002. Accessed March 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf

14. U.S. Food and Drug Administration. Tretinoin (Vesanoid) drug label. Updated 2004. Accessed March 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20438s004lbl.pdf

15. Yaghi M, McMullan P, Truong TM, et al. Safety of dermatologic medications in pregnancy and lactation: An update-Part II: Lactation. J Am Acad Dermatol. 2024;91(4):651-668. doi:10.1016/j.jaad.2023.10.071